Nicotinamide phosphoribosyltransferase (NAMPT; also known as visfatin and pre-B-cell colony-enhancing factor 1 (PBEF)) is an enzyme that catalyzes the condensation of nicotinamide (NaM) with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide. This is the first and rate-limiting step in one biosynthetic pathway that cells use to make nicotinamide adenine dinucleotide (NAD+). NAD+ is a critical cofactor for multiple enzymes involved in cell metabolism and homeostasis.
Inhibition of NAMPT results in the lowering of cellular concentrations of NAD+(Beauparlant et al (2007) AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2007 Oct. 22-26 Abstract nr A82; and Roulson et al (2007) AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2007 Oct. 22-26 Abstract nr A81). Cancer cells have a higher basal turnover of NAD+ and also display higher energy requirements compared with normal cells. Small-molecule inhibitors of NAMPT have been shown to cause depletion of intracellular NAD+ levels and ultimately induce tumor cell death (Hansen, C M et al. Anticancer Res. 20, 42111-4220, 2000) as well as inhibit tumor growth in xenograft models (Olese, U. H. et al. Mol Cancer Ther. 9, 1609-1617, 2010).
Compounds of the invention inhibit the activity of NAMPT, and therefore, may be useful for the treatment of cancer. Cases where NAMPT inhibition has been linked to cancer, a disease where the compounds of the invention may have a therapeutic benefit, include but are not limited to colorectal cancer (Van Beijnum, J. R. et al. Int. J. Cancer 101, 118-127, 2002) and NAMPT is involved in angiogenesis (Kim, S. R. et al. Biochem. Biophys. Res. Commun. 357, 150-156, 2007), multiple myeloma (Chauhan, D. et al., Blood, 2012, 120, 3519-3529), breast cancer (Lord, C. J. EMBO Mol. Med. 2012, 4, 1087-1096), leukemia (Thakur, B. K. et al. Int. J. Cancer 2013, 132, 766-774), non-small cell lung (NSCL) cancer (Okumura, S. J. Thorac. Oncol. 2012, 7, 49-56), gastric cancer (Bi, T. Q. et al. Oncol. Rep. 2011, 26, 1251-1257), neuroblastoma (Travelli, C. et al. J. Pharmacol. Exp. Ther. 2011, 338, 829-840), bladder cancer (Yang, H. J. Exp. Biol. Med. 2010, 235, 869-876), mammary carcinoma (Muruganandham, M. et al. Clin. Cancer Res. 2005, 11, 3503-3513), liver carcinoma (Hasmann, M. Cancer Res. 2003, 63, 7436-7442), renal carcinoma (Drevs, J. Anticancer Res. 2003, 23, 4853-4858, cervix adenocarcinoma (Pittelli, M. et al. J. Biol. Chem. 2010, 285, 34106-34114), glioma (Pitelli, N. et al), lymphoma (Le, A. et al. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 2037-2042), pancreatic cancer (Le, A. et al.), ovarian cancer (Olesen, U. H. et al. Mol. Cancer Ther. 2010, 9, 1609-1617), melanoma (Maldi, E. et al. Pigm. Cell Melanoma Res. 2013, 26, 144-146), prostate cancer (Zerp, S. F. et al. Radiother. and Oncol. 10, 2014, 110, 348).
Other cases, where a compound of the invention may have a therapeutic benefit as a NAMPT inhibitor, include inflammatory conditions such as rheumatoid arthritis, inflammatory bowl disease, asthma, COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis, sepsis, lupus, spinal cord injury and infection (Galli, M. et al Cancer Res. 70, 8-11, 2010). For example, NAMPT is the predominant enzyme in T and B lymphocytes. Selective inhibition of NAMPT leads to NAD+ depletion in lymphocytes blocking the expansion that accompanies autoimmune disease progression whereas cell types expressing the other NAD+ generating pathways might be spared. A small molecule NAMPT inhibitor (FK866) has been shown to selectively block proliferation and induce apoptosis of activated T cells and was efficacious in animal models of arthritis (collagen-induced arthritis) (Busso, N. et al. Plos One 3, e2267, 2008). FK866, a small molecule NAMPT inhibitor, ameliorated the manifestations of experimental autoimmune encephalomyelitis (EAE), a model of T-cell mediated autoimmune disorders. (Bruzzone, S et al. Plos One 4, e7897, 2009). NAMPT activity increases NF-kB transcriptional activity in human vascular endothelial cell, resulting in MMP-2 and MMP-9 activation, suggesting a role for NAMPT inhibitors in the prevention of inflammatory mediated complications of obesity and type 2 diabetes (Adya, R. et. Al. Diabetes Care, 31, 758-760, 2.
Clearly, it would be beneficial to provide novel NAMPT inhibitors that possess good therapeutic properties, especially for the treatment of cancer, inflammatory conditions, and T-cell mediated autoimmune disease.